Regional expression of the proto-oncogene c-fos was mapped by in situ hybridization in rat brain sections from animals with amygdala-kindled seizures. Previously, two patterns of c-fos induction were observed during initial stages of amygdala kindling, one involving only hippocampal and amygdala inductions and a second involving cortical and amygdala regions with no hippocampal c-fos induction. We have established a direct correlation of hippocampal c-fos induction to a longer duration of afterdischarges. Also, in rats exhibiting running fits (associated with their fully developed kindled seizure), c-fos was also increased in the dorsal aspect of the inferior colliculus, a brain area known to be involved with running fits. The interaction of acute benzodiazepine (BZ) and chronic caffeine (CAF) treatment in the induction of c-fos mRNA by a CAF challenge was investigated by rats. Acute CAF-induced c-fos was limited to the striatum and olfactory tubercle in the absence of seizures. However, with a CAF- induced seizure, c-fos was also elevated in the hippocampus and olfactory bulb. Acute pretreatment with Ro 5-4864 (an agonist selective for central- type BZ receptors) had no effect on CAF-induced c-fos in the absence of seizure. With CAF-induced seizure, Ro5-4864 (but not Ro-15-1788) potentiated CAF-induced c-fos in striatum, hippocampus and olfactory bulb and also significantly increased c-fos in cortical regions. Chronic CAF treatment reduced basal levels of c-fos with no effect on the amount of striatal c-fos induced by a CAF challenge. Withdrawal from CAF restored striatal c-fos levels to control levels, suggesting that CAF-induced c-fos and CAF-induced seizures may involve an interaction with the peripheral- type BZ receptor system. Studies on the regional expression of peripheral- type benzodiazepine receptor (PBR) mRNA in rat brain were started. Although only in the preliminary stages, it appears that cocaine treatment may decrease PBR antisense mRNA without affecting the sense strand. The effects of lidocaine and other drugs altering CNS excitability will be investigated as well.